DESCRIPTION: (Applicant's Abstract) The substantial health risk posed by chronic cocaine use has prompted a serious research effort to identify the neurobiological substrates that underlie the motivational aspects of drug seeking and drug relapse. Research in this area has concentrated on the nucleus accumbens (NAc) which is considered to be an integral component in the link between motivation and action. The NAc receives afferents from several neurotransmitter systems (e.g. dopamine, serotonin, glutamate) and each of these has been implicated in drug reinforcement. Despite this substantial progress, our understanding of the neurochemical mechanisms involved in the motivational aspects of drug seeking remains incomplete. The NAc is known to contain cholinergic interneurons whose activity may have important motivational consequences. The first specific aim of this research is to identify the impact of cocaine self-administration on acetylcholine (ACh) release within the NAc and, as a motoric control, the dorso-lateral striatum. Sprague-Dawley rats will be implanted with intravenous catheters and trained to lever-press for infusions of cocaine. Microdialysis will be used to measure ACh at four time points: 1) during initial exposure to cocaine, 2) after 2 weeks of daily self-administration, 3) after 10 days of withdrawal and finally 4) during reinstated self-administration. The second aim of these experiments is to determine the responsiveness of ACh interneurons within the NAc to GABAergic and dopaminergic drugs following 2 weeks of cocaine self-administration and after ten days of withdrawal. Microdialysis probes will be used to administer drugs into the NAc while ACh release is measured. The third aim of this research is to characterize the extent to which ACh modulates cocaine self-administration. Rats will be trained to lever-press for intravenous infusions of cocaine on a progressive ratio schedule of reinforcement. Micro-infusions of ACh agonists and antagonists will be delivered bilaterally into the NAc prior to drug availability. Responding on drug-active and inactive levers will be measured for five hours following infusions. Selective increases in responding on the drug-active lever should indicate an increase in the motivation to obtain cocaine while decreases in responding would signal a suppression. It is hoped that these results will further our understanding of the involvement of cholinergic mechanisms in drug-seeking and potentially to the development of clinically efficacious treatments for drug craving and relapse.